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Investigating the role of ADAM17 in human cytomegalovirus infection

Trinca, Anzelika 2023. Investigating the role of ADAM17 in human cytomegalovirus infection. PhD Thesis, Cardiff University.
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Human cytomegalovirus (HCMV) is one of the most widespread, highly successful herpesviruses, establishing a life-long viral infection in humans. HCMV has been described as a paradigm of immune evasion able to manipulate many immune functions in the host. One of the host manipulation strategies employed by HCMV is the downregulation of a disintegrin and metalloproteinase 17 (ADAM17) – an important ectodomain shedding protease responsible for cleaving over a 100 substrates including many immunoregulatory molecules, such as receptors, cytokines, chemokines and adhesion molecules. Synergistic action of viral UL148 and UL148D result in a rapid ADAM17 downregulation from the surface of HCMV-infected cells. This thesis explores the mechanism and consequences of ADAM17 impairment by HCMV genes UL148 and UL148D, demonstrating the significance of ADAM17 downregulation in HCMV infection. UL148 and UL148D were shown to interfere with ADAM17 maturation, resulting in expression of only the intracellular immature precursor, and absence of mature ADAM17 on the surface of wildtype HCMV-infected cells. The mechanism of ADAM17 impairment was shown to be complex, suggesting that UL148 and UL148D act to downregulate ADAM17 via distinct mechanisms, with a possibility of a third viral gene involved in the process. The global consequences of ADAM17 downregulation by HCMV were analysed using proteomics and validated using biochemical and flow cytometric techniques, revealing that this virus manipulation impacted multiple cell surface and secreted host proteins. This included stabilisation of Vasorin, Jagged1, Nectin1 and Endothelial protein C receptor (EPCR), as well as a number of viral proteins. Other known ADAM17 targets were not stabilised, suggesting specific control by HCMV. The functional consequences of these changes to the levels of secreted and soluble proteins were tested and revealed the importance of ADAM17 impairment in regulatory T cell and NK cell function; however with so many ADAM17 substrates stabilised on cell surface as a result of HCMV infection, many other pathways are likely also affected.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 13 April 2023
Last Modified: 14 Apr 2023 09:50

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